Tuberculosis is a world-wide health threat. Agents that can effectively kill this bacterium while maintaining moderate cytotoxicity hold promise to treat this disease in humans. Given the advent of both multi-drug resistant (MDR) and completely drug resistant (XDR) strains of this pathogen, development of a “next-generation” series of small molecules to treat this disease could provide great benefits.
Naamidine A, a natural product isolated from the marine sponge Lucetta chagosensis, displays anti-proliferative activity against both Mycobacterium tuberculosis (IC50=0.94 μM or 0.41 μg/mL) and Candida albicans (MIC100=0.78 M). The related natural products kealiinines B and C also display anti-tubercular activity (IC50=8.9 μM and 42 μM respectively). Naamidine A has been shown to be relatively well tolerated in vivo for mouse models, with a maximum tolerated dose of 25 mg/Kg (see Ireland et al., J. Med. Chem. 1998, 41, 3909). Further, in CEM-TART cells, the IC50=34.8 μM, which indicates a selectivity ratio of 37.

Naamidine A also displays selective anti-cancer activity of therapeutic interest. See, e.g., U.S. Pat. No. 5,574,057. Many cancer drugs are nearly indiscriminate in their cytotoxicity and affect healthy and tumor cells comparably. The resulting narrow therapeutic treatment windows limit both the amount of drug that can be administered to patients and the duration of treatment, reducing the overall efficacy of the therapy. Additionally, the adverse side effects arising from low therapeutic indices can necessitate additional palliative care efforts and further burden patient recovery. In contrast, naamidine A selectively inhibits proliferation of cancerous cells, thereby providing a potential advantage over less selective agents.
Naamidine A's activity may partially arise from its ability to coordinate zinc. Zinc is an essential trace metal; it is estimated that 10% of the proteome may bind zinc, with 40% of these proteins functioning as transcription factors and the remaining 60% operating in an enzymatic or an ion transport capacity. Andreini et al. J Proteome Res 2005; 5(1): 196-201. Perturbations in zinc homeostasis are correlated with various disease states, and in the case of breast cancer, increased zinc levels have been observed in malignant breast tissue compared to nonmalignant tissue. Margalioth et al. Cancer 1983; 52(5):868-72; Geraki et al. Phys Med Biol 2004; 49(1):99. As such, exploiting differences in zinc homeostasis between healthy and diseased tissue may provide new avenues for the development of anti-cancer therapeutics.
Despite naamidine A's promise as a therapeutic agent, its 1H-imidazole-2,5-dione substituent complicates its preparation and evaluation as a possible drug. Simpler, easier-to-make analogs of naamidine A possessing therapeutically interesting activity, especially anti-tubercular or anti-cancer activity, would present advantages over naamidine A itself, especially if the analogs were available by an efficient synthetic route.
The present invention's 2-aminoimidazole compositions and methods present embodiments with these and other advantages.